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Tandem Gene Duplications Drive Divergent Evolution of Caffeine And Xu et al. BMC Biology (2020) 18:63 https://doi.org/10.1186/s12915-020-00795-3 RESEARCH ARTICLE Open Access Tandem gene duplications drive divergent evolution of caffeine and crocin biosynthetic pathways in plants Zhichao Xu1,2†, Xiangdong Pu1†, Ranran Gao1, Olivia Costantina Demurtas3, Steven J. Fleck4, Michaela Richter4, Chunnian He1,2, Aijia Ji1, Wei Sun5, Jianqiang Kong6, Kaizhi Hu7, Fengming Ren1,7, Jiejie Song8, Zhe Wang6, Ting Gao8, Chao Xiong5, Haoying Yu1, Tianyi Xin1, Victor A. Albert4,9, Giovanni Giuliano3*, Shilin Chen2,5* and Jingyuan Song1,2,10* Abstract Background: Plants have evolved a panoply of specialized metabolites that increase their environmental fitness. Two examples are caffeine, a purine psychotropic alkaloid, and crocins, a group of glycosylated apocarotenoid pigments. Both classes of compounds are found in a handful of distantly related plant genera (Coffea, Camellia, Paullinia, and Ilex for caffeine; Crocus, Buddleja, and Gardenia for crocins) wherein they presumably evolved through convergent evolution. The closely related Coffea and Gardenia genera belong to the Rubiaceae family and synthesize, respectively, caffeine and crocins in their fruits. Results: Here, we report a chromosomal-level genome assembly of Gardenia jasminoides, a crocin-producing species, obtained using Oxford Nanopore sequencing and Hi-C technology. Through genomic and functional assays, we completely deciphered for the first time in any plant the dedicated pathway of crocin biosynthesis. Through comparative analyses with Coffea canephora and other eudicot genomes, we show that Coffea caffeine synthases and the first dedicated gene in the Gardenia crocin pathway, GjCCD4a, evolved through recent tandem gene duplications in the two different genera, respectively. In contrast, genes encoding later steps of the Gardenia crocin pathway, ALDH and UGT, evolved through more ancient gene duplications and were presumably recruited into the crocin biosynthetic pathway only after the evolution of the GjCCD4a gene. (Continued on next page) * Correspondence: [email protected]; [email protected]; [email protected] †Zhichao Xu and Xiangdong Pu contributed equally to this work. 3Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Casaccia Res. Ctr, 00123 Rome, Italy 2Engineering Research Center of Chinese Medicine Resource, Ministry of Education, Beijing 100193, China 1Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People’s Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xu et al. BMC Biology (2020) 18:63 Page 2 of 14 (Continued from previous page) Conclusions: This study shows duplication-based divergent evolution within the coffee family (Rubiaceae) of two characteristic secondary metabolic pathways, caffeine and crocin biosynthesis, from a common ancestor that possessed neither complete pathway. These findings provide significant insights on the role of tandem duplications in the evolution of plant specialized metabolism. Keywords: Crocin biosynthesis, Caffeine biosynthesis, Gardenia jasminoides, Coffea canephora, Genomics, Carotenoid cleavage dioxygenases, Aldehyde dehydrogenases, UDP-glucosyltransferases, N-Methyltransferases Background molecules, flower and fruit pigments, and regulators of Flowering plants have evolved a diverse array of secondary membrane fluidity [14]. They have been reported to have metabolites to repel pathogens and predators, attract polli- anticancer, anti-inflammatory, antioxidant, and anti- nators, and drive ecosystem functions. In many cases, the diabetic activities and to be beneficial in the treatment genomic context for the evolution of specialized plant com- of central nervous system and cardiovascular diseases pounds involves tightly linked clusters of genes, usually [15, 16]. Crocin biosynthesis in saffron stigmas is initi- containing nonhomologous gene families, that together ated by carotenoid cleavage dioxygenase 2 (CsCCD2), control novel biosynthetic pathways [1–3]. A few important which cleaves zeaxanthin to produce crocetin dialdehyde metabolic clusters involve only tandem duplicates within [17]. The aldehyde dehydrogenase CsALDH3I1 and the single gene families, such as the N-methyltransferase UDP-glucosyltransferase CsUGT74AD1 perform, re- (NMT) genes that control caffeine biosynthesis in the coffee spectively, the dehydrogenation of crocetin dialdehyde to plant [4], and the cytochrome p450 genes encoding the 2,4- crocetin and its glycosylation to crocins 1 and 2′ [18]. dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) The UGT mediating the formation of more highly glyco- metabolic cluster of maize, which produces an important sylated crocins is still uncharacterized [18]. In Buddleja defense compound [5, 6]. Tandem gene duplicate clusters flowers, only the zeaxanthin cleavage step has been char- originally arise as copy number variants (CNVs) in popula- acterized, and it is mediated by BdCCD4.1 and tions that later become fixed within species by evolving split BdCCD4.3 [19]. Thus, it appears that crocin biosynthesis or novel functions [7]. Given the ongoing nature of CNV in eudicots (Buddleja) and monocots (Crocus) has production during evolution, genome sequencing of closely evolved through the convergent evolution of different related plants harboring distinct secondary metabolite pro- CCD subclasses (CCD2 and CCD4, respectively) that files holds great promise for understanding the stepwise have acquired the capacity to cleave zeaxanthin at the at evolution of important tandem duplicate clusters. the 7/8,7′/8′ positions to produce crocetin dialdehyde. The Gardenia genus, which is among the most com- In G. jasminoides, crocins are accumulated in green and monly grown horticultural plants worldwide and is val- red fruits (Fig. 1b). The Gardenia crocin biosynthesis ued for the strong, sweet fragrance of its flowers, pathway has not yet been elucidated, in spite of the avail- belongs to the family Rubiaceae. In this large family of ability of transcriptome data [20]. Two G. jasminoides angiosperms, only the Coffea canephora (robusta coffee) UGTs, GjUGT94E5 and GjUGT75L6, are able to catalyze genome has been sequenced to date [4]. The Chinese the two-step conversion of crocetin into crocins in vitro species Gardenia jasminoides (gardenia) has been culti- [21]. However, the expression profiles of the correspond- vated for at least 1000 years and was introduced to ing genes are not consistent with their proposed role in Europe and America in the mid-eighteenth century. The crocin biosynthesis in G. jasminoides fruits [20]. Addition- fruits of G. jasminoides, whose major bioactive constitu- ally, the lack of genomic information for crocin-producing ents are genipin and crocins, were used as an imperial species hampers the elucidation of the mechanisms under- dye for royal costumes during the Qin and Han dynas- lying the molecular evolution of crocin biosynthesis. Re- ties in China and are recorded in the Chinese cently, sequencing of the C. canephora (Rubiaceae) and Pharmacopoeia [8, 9]. Unlike coffee, gardenia does not Camellia sinensis (Theaceae) genomes has shown that the accumulate caffeine. However, in a pattern similar to the synthesis of caffeine, a purine alkaloid, has evolved inde- scattered instances of convergent caffeine biosynthesis pendently in the two genera through tandem duplication among several angiosperm families [4, 10], crocins are and neofunctionalization of different N-methyltransferase found in the flowers of the distantly related plants Bud- (NMT) ancestral genes [4]. dleja davidii (Buddlejaceae) and in the stigmas of Crocus Here, we report a chromosome-level assembly of the sativus (saffron) (Iridaceae) (Fig. 1a). highly heterozygous G. jasminoides genome, using a Apocarotenoids, derived from carotenoids by oxidative combination of Illumina short reads, Oxford Nanopore cleavage [11–13], play crucial roles in plants as signaling (ONT) long reads, and Hi-C scaffolding. The genes Xu et al. BMC Biology (2020) 18:63 Page 3 of 14 involved in the crocin biosynthesis pathway were identi- The purged assembly was 534.1 Mb long with a contig fied through functional assays, and the molecular evolu- N50 of 1.0 Mb (Additional file
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